The present invention relates to a practically valuable and novel process for producing an optically active alcohol, which comprises a step of subjecting a xcex2-keto ester to an asymmetric reduction in the presence of an optically active catalyst.
Hitherto, the following are known as methods for synthesizing optically active 4,4,4-trifluoro- or 4,4,4-trichloro-3-hydroxybutanoate esters: 1) a method of obtaining an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester by selective enzymatic hydrolysis of the ester group of a 4,4,4-trifluoro-3-hydroxybutanoate ester, which is a racemic mixture, used as a starting material using a lipase and extraction of unhydrolyzed (R)-enantiomer (JP-A-8-289799); 2) a method of obtaining a hydrolyzed (R)-enantiomer by acetylation of the hydroxyl group of a 4,4,4-trifluoro-3-hydroxybutanoate ester, which is a racemic mixture, and successive enzymatic hydrolysis with a lipase (J. Org. Chem., Vol. 63, pp. 8058-8061 (1998)); 3) a method of obtaining an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester by ester exchange through a reaction of an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester with an alcohol in the presence of an ammonium salt of a sulfonic acid derivative (JP-A-3-151348); 4) a method of obtaining an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester or 4,4,4-trichloro-3-hydroxybutanoate ester by reduction of a 4,4,4-trifluoro-3-oxobutanoate ester or 4,4,4-trichloro-3-oxobutanoate ester using baker""s yeast (Tetrahedron Asymmetry, Vol. 9, pp. 285-292 (1997)); 5) a method of obtaining an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester by asymmetric ester exchange of a 4,4,4-trifluoro-3-hydroxybutanoate ester, which is a racemic mixture, with a vinyl ester using an enzyme derived from a microorganism or wheat germ (JP-A-5-219986); 6) a method of obtaining an optically active 4,4,4-trifluoro-3-hydroxybutanoate ester by hydrogenation of a 4,4,4-trifluoro-3-oxobutanoate ester in the presence of a nickel catalyst supporting an optically active compound (JP-A-9-268146); 7) a method of obtaining an optically active 4,4,4-trichloro-3-hydroxybutanoate ester by asymmetric hydrogenation of a 4,4,4-trichloro-3-oxobutanoate ester using an optically active BINAP catalyst (JP-A-63-310847); 8) a method of conducting a reaction of a 4,4,4-trifluoro-3-hydroxybutanoate ester, which is a racemic mixture, with acetic anhydride using a lipase to obtain an unreacted 4,4,4-trifluoro-3-hydroxybutanoate ester as an optically active one (JP-A-3-254694); and so forth.
However, in the above synthetic methods of optically active alcohols, the following have been found to be problems: the synthetic methods using enzymes require tedious operations and process controls and have limitations on kinds of reaction substrates, and also alcohols having an absolute configuration are restricted to specific ones; in the case of using a 4,4,4-trifluoro-3-hydroxybutanoate ester, which is a racemic mixture, as a reaction substrate, the yield of optically active 4,4,4-trifluoro-3-hydroxybutanoate ester having a desired configuration is 50% or less; in the case of reducing a 4,4,4-trifluoro-3-oxobutanoate ester or a 4,4,4-trichloro-3-oxobutanoate ester using baker""s yeast, the resulting 4,4,4-trifluoro-3-hydroxybutanoate ester or 4,4,4-trichloro-3-hydroxybutanoate ester has a low optical purity; and a 4,4,4-trifluoro-3-hydroxybutanoate ester or 4,4,4-trichloro-3-hydroxybutanoate ester obtainable by asymmetric hydrogenation using a nickel catalyst supporting an optically active compound or an optically active Ru-BINAP catalyst has an insufficient optical purity. In particular, in the fields of medicines and functional materials, it is important to obtain a compound having a specific absolute configuration in a good optical purity, and thus it is necessary to solve the problems in the above methods.
An object of the invention is to provide a novel production process capable of obtaining an optically active alcohol having a desired absolute configuration in a high optical purity by subjecting a xcex2-keto ester such as a 3-perfluoroalkyl-3-oxopropionate ester or a 3-trichloroalkyl-3-oxopropionate ester to asymmetric reduction in simple and convenient operations.
Under such circumstances, as a result of extensive studies, the present inventors have found that, by subjecting a xcex2-keto ester represented by the general formula (I) such as a 4,4,4-trifluoro-3-oxobutanoate ester or a 4,4,4-trichloro-3-oxobutanoate ester to hydrogen-transfer type asymmetric reduction in the presence of an optically active ruthenium-diamine complex represented by the general formula (II), a corresponding optically active alcohol is obtained in a high optical purity. Based on a result of further examinations, they have accomplished the invention.
Heretofore, the methods of obtaining an optically active hydroxy compound by subjecting a carbonyl compound to asymmetric hydrogen-transfer type reduction using an optically active ruthenium-diamine complex represented by the general formula (II) have been known (JP-A-10-236986, J. Am. Chem. Soc., Vol. 118, pp. 2521-2522 (1996)). However, these methods are a method for producing an optically active alcohol having an acetylene bond by subjecting a carbonyl compound having an acetylene bond to asymmetric hydrogen-transfer type reduction and a method of an optically active hydroxy compound by subjecting a carbonyl compound such as an aryl alkyl ketone to asymmetric hydrogen-transfer type reduction. Although a description of a xcex2-keto acid derivative exists in JP-A-10-236986, there is no concrete example with regard to the compound and also, when an acetoacetate ester as a xcex2-keto acid derivative has been subjected to asymmetric reduction using an optically active ruthenium-diamine complex, no reduction has proceeded. However, the inventors have found that, in the case that a 4,4,4-trifluoro-3-oxobutanoate ester or a 4,4,4-trichloro-3-oxobutanoate ester is subjected to an asymmetric hydrogen-transfer type reduction, a corresponding optically active alcohol is obtained in a high optical purity, and as a result of further extensive examinations, they have accomplished the invention.
Namely, the invention relates to:
(1) a process for producing an optically active alcohol represented by the general formula (III): 
(wherein * represents an asymmetric carbon atom, R1 represents a C1-C10 linear or branched perfluoroalkyl or perchloroalkyl group and R2 represents a C1-C6 lower alkyl group or benzyl group which may have a substituent), which comprises a step of subjecting a xcex2-keto ester represented by the general formula (I): 
(wherein R1 and R2 each has the same meaning as described above) to a hydrogen-transfer reaction in the presence of an optically active ruthenium-diamine complex represented by the general formula (II): 
(wherein * represents an asymmetric carbon atom, R3 and R4 are the same or different and each represents an alkyl group or phenyl group or a cycloalkyl group which may have an alkyl group, or R3 and R4 may form an alicyclic ring unsubstituted or substituted by an alkyl group together with adjacent carbon atoms, R5 represents methanesulfonyl group; trifluoromethanesulfonyl group; benzene sulfonyl group or naphthyl group which may be substituted by an alkyl group, an alkoxy group, or a halogen atom; camphorsulfonyl group; an alkoxycarbonyl group; or benzoyl group which may be substituted by an alkyl group, R6 represents hydrogen atom or an alkyl group, Ar represents an aromatic compound which may be substituted by an alkyl group, and X represents a halogen atom),
(2) the process for producing an optically active alcohol as described in above (1), wherein R1 is a C1-C7 linear or branched perfluoroalkyl or perchloroalkyl group,
(3) the process for producing an optically active alcohol as described in above (1), wherein R3 and R4 of the optically active ruthenium-diamine complex (II) are each phenyl group, R6 is hydrogen atom, and X is chlorine atom,
(4) the process for producing an optically active alcohol as described in above (1) or (2), wherein Ar of the optically active ruthenium-diamine complex (II) is p-cymene, benzene, or mesitylene, and
(5) the process for producing an optically active alcohol as described in any one of above (1) to (4), wherein the reaction is conducted in the presence of a hydrogen-donating substance.
In explanation of the xcex2-keto ester to be used in the invention with reference to the general formula (I), R1 in the formula is a C1-C10 linear or branched perfluoroalkyl or perchloroalkyl group, and more specifically, pentafluoroethyl group, heptafluoropropyl group, nonafluorobutyl group, undecafluoropentyl group, tridecafluorohexyl group, pentadecafluoroheptyl group, trifluoromethyl group and trichloromethyl group are mentioned.
Examples of R2 specifically include C1-C6 alkyl group such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, and 3-hexyl group, and benzyl group which may have a substituent, such as benzyl group, p-methylbenzyl group, p-methoxybenzyl group, and p-nitorobenzyl group. Particularly, preferred are C1-C4 alkyl groups, i.e., methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, and tert-butyl group.
In explanation of the optically active ruthenium-diamine complex to be used in the invention with reference to the general formula (II), R3 and R4 in the formula are the same or different and each is (1) an alkyl group or (2) phenyl group or a cycloalkyl group which may have an alkyl group, or (3) R3 and R4 may form an alicyclic ring unsubstituted or substituted by an alkyl group together with adjacent carbon atoms. More specifically, R3 and R4 each is an alkyl group, preferably a C1-C4 alkyl group, and may be a linear or branched alkyl group. Examples of R3 and R4 specifically include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, and tert-butyl group. More preferred are methyl group, ethyl group, n-propyl group and isopropyl group.
In the case that R3 and R4 form an alicyclic ring unsubstituted or substituted by an alkyl group together with adjacent carbon atoms, the ring may be a five- to seven-membered ring, and the alkyl group by which the ring is substituted may be, for example, a C1-C4 alkyl group, specifically methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, isobutyl, tert-butyl group, or the like. Particularly preferred is methyl group.
R3 and R4 in the case that R3 and R4 is phenyl group which may have an alkyl group specifically include phenyl, o-, m-, or p-tolyl group, and o-, m-, or p-anisyl group. More preferred specific example is the case that R3 and R4 each is phenyl group or that R3 and R4 represent tetramethylene group (xe2x80x94(CH2)4xe2x80x94) in combination.
R5 represents (1) methanesulfonyl group, (2) trifluoromethanesulfonyl group, (3) benzene sulfonyl group or naphthyl group which may be substituted by an alkyl group (e.g., a C1-C3 alkyl group), an alkoxy group (e.g., a C1-C3 alkoxy group), or a halogen atom, (4) camphorsulfonyl group, (5) an alkoxycarbonyl group, or (6) benzoyl group which may be substituted by an alkyl group (e.g., a C1-C4 alkyl group).
R5 as benzenesulfonyl group which may be (e.g., a C1-C4 alkyl group) substituted by a C1-C3 alkyl group, a C1-C3 alkoxy group, or a halogen atom is specifically benzenesulfonyl group, o-, m-, or p-toluenesulfonyl group, o-, m-, or p-ethylbenzenesulfonyl group, o-, m-, or p-isopropylbenzenesulfonyl group, o-, m-, or p-tert-butylbenzenesulfonyl group, o-, m-, or p-methoxybenzenesulfonyl group, o-, m-, or p-ethoxybenzenesulfonyl group, o-, m-, or p-chlorobenzenesulfonyl group, o-, m-, or p-fluorobenenesulfonyl group, 2,4,6-trimethylbenzenesulfonyl group, 2,4,6-triisopropylbenezenesulfonyl group, or the like, and more preferred is benzenesulfonyl group or p-toluenesulfonyl group.
R5 as a C1-C4 alkoxycarbonyl group is specifically methoxycarbonyl group, ethoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, or the like, and more preferred is methoxycarbonyl group or tert-butoxycarbonyl group.
R5 as benzoyl group which may be substituted by a C1-C4 alkyl group is specifically benzoyl group, o-, m-, or p-methylbenzoyl group, o-, m-, or p-ethylbenzoyl group, o-, m-, or p-isopropylbenzoyl group, o-, m-, or p-tert-butylbenzoyl group, or the like, and more preferred is benzoyl group or p-methylbenzoyl group.
In the most preferred specific examples, R5 is methanesulfonyl group, trifluoromethanesulfonyl group, benzenesulfonyl group, or p-toluenesulfonyl group.
R6 which represents hydrogen atom or a C1-C4 alkyl group is specifically hydrogen, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, or the like, and more preferred is hydrogen or methyl group.
Furthermore, the aromatic compound represented by Ar, which may be substituted by an alkyl group (preferably a C1-C4 alkyl group), in the optically active ruthenium-diamine complex (II) includes, for example, benzene, toluene, xylene, mesitylene, hexamethylbenzene, ethylbenzene, tert-butylbenzene, p-cymene, cumene, and the like. Preferred is benzene, mesitylene, or p-cymene.
The amount of the above optically active ruthenium-diamine complex in the invention varies depending on the size of the reaction vessel and economical efficiency, but the complex is used in a molar ratio of about 1/10 to 1/10000, preferably about 1/100 to 1/5000 relative to the substrate compound of the general formula (I).
In the invention, it is usually preferable to allow to exist a hydrogen-donating substance in the reaction system. The hydrogen-donating substance for use in the production of an optically active hydroxy compound by hydrogen-transfer type reduction in the invention is an organic or inorganic compound, which may be any compound as far as it can donate hydrogen in the reaction system through a thermal action or catalytic action.
The hydrogen-donating substance is not particularly limited to a specific kind, but preferred is formic acid or a salt thereof, e.g., a combination of formic acid and an amine, hydroquinone, phosphorous acid, or the like. Of these, preferred is formic acid or a combination of formic acid and an amine. The amine includes trimethylamine, triethylamine, and the like. In the case that formic acid or a combination of formic acid and an amine is used as a hydrogen source, a solvent may not be employed. In the reaction, any solvent can be employed unless it inhibits the reaction. As the solvent, specifically, use may be made of alcohol compounds such as methanol and ethanol; aromatic compounds such as toluene and xylene; aliphatic ester compounds such as methyl acetate, ethyl acetate, and butyl acetate; halogenated compounds such as dichloromethane; aliphatic compounds such as hexane and heptane; ether compounds such as tetrahydrofuran and diethyl ether; other organic compounds such as dimethyl sulfoxide, N,N-dimethylformamide, and acetonitrile.
The reaction temperature may be about xe2x88x9220 to about 100xc2x0 C., and in view of the economic efficiency, the reaction can be conducted more practically in the vicinity of room temperature, i.e., about 25 to about 40xc2x0 C.
The reaction period of time varies depending on the reaction conditions such as substrate concentration, catalyst concentration, and temperature, but the reaction generally finishes within several minutes to 100 hours.
According to the invention, the compound represented by the general formula (III) is obtained in high optical purity. For example, in the case that the compound of the formula (I) is shown by CF3xe2x80x94COxe2x80x94CH2xe2x80x94COOR2, and the compound of the formula (II) has a configuration of (R,R), the aimed product represented by the formula (III) is obtained as a (R)-(+)-body.
The following will explain the invention in further detail with reference to Examples, but the invention is not limited to these Examples.
The optically active ruthenium-diamine complex used in Examples was prepared by the method described in JP-A-10-130289 or J. Am. Chem. Soc., Vol. 118, pp. 2521-2522 (1996).
Moreover, Commercial products (products manufactured by Tokyo Kasei Kogyo Co., Ltd.) were used as methyl 4,4,4-trifluoro-3-oxobutanoate, ethyl 4,4,4-trifluoro-3-oxobutanoate, isopropyl 4,4,4-trifluoro-3-oxobutanoate, and ethyl 4,4,4-trichloro-3-oxobutanoate used in Examples.
Methyl 3-oxo-4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-pentadecafluorodecanoate used in the Example was prepared by the procedure described in the literature (J. Fluorine Chem., Vol. 20, 187-202 (1982)).
Furthermore, the chemical purity, conversion, and optical purity were determined by the apparatus and methods shown in the following.
Additionally, in Examples and Referential Examples, Ts represents toluenesulfonyl group.
Chemical Purity and Conversion: